Biomarkers of Hormone Therapy Response in a Multicenter Prostate Cancer Trial Abstract Androgen deprivation therapy (ADT) is the cornerstone of treatment for metastatic prostate cancer (mPC), and new hormonal agents have recently improved survival for some patients. However, the use of ADT remains empiric, and as novel hormonal agents continue to emerge there is a growing need for biomarkers to guide their optimal use. Preliminary data from our group and others suggest that variations in genomic and expression profiles within the androgen pathway are significantly associated with clinical response to hormonal agents. Here, we propose to expand upon our findings by undertaking a comprehensive analysis of tumor and host androgen pathway genes in men initiating ADT for mPC. We hypothesize that the initial response and subsequent resistance to ADT is governed by the genetic and expression profiles of the androgen pathway. We will test this hypothesis in a Phase III SWOG- sponsored trial of 1,500 men with mPC initiating ADT with leuprolide (LHRH agonist) and either bicalutamide (anti-androgen) or orteronel (novel CYP17,20 lyase inhibitor). Specifically, we will identify androgen pathway phenotypes associated with therapy response, defined as PSA at 7 months and progression-free survival. The androgen pathway will be analyzed in a CLIA- certified setting using patient samples obtained during the trial as follows: I Aim 1, we will analyze germline sequence variation in androgen pathway genes using white blood cells; in Aim 2, we will analyze somatic sequence variation as well as mRNA expression of androgen pathway genes in circulating tumor cells (CTCs) at study onset and upon castration resistance; in Aim 3, we will analyze somatic sequence variation and mRNA expression of androgen pathway genes in primary tumor specimens. In an exploratory subset of responders and non- responders, whole transcriptomes will be sequenced from CTCs and primary tumors to identify additional novel gene candidates associated with response to ADT. Collectively, these analyses will yield an unprecedented, comprehensive picture of how clinical response to hormonal therapy is associated with variations in androgen pathway biology in the host (Aim 1), in metastatic cancer cells (Aim 2), and in the primary tumor (Aim 3). As importantly, this SWOG- led study will offer a unique opportunity both to identify and to validate reliable biomarkers give its exceptionally large cohort size and treatment homogeneity. New predictors of response based on androgen pathway biology will advance the mechanism-driven, individualized use of hormonal therapy and ultimately will promote more effective precision management of patients with mPC.